IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models

Helena Ågerstam; Nils Hansen; Sofia von Palffy; Carl Sandén; Kristian Reckzeh; Christine Karlsson; Henrik Lilljebjörn; Niklas Landberg; Maria Askmyr; Carl Högberg; Marianne Rissler; Kimmo Porkka; Hans Wadenvik; Satu Mustjoki; Johan Richter; Marcus Järås; Thoas Fioretos

doi:10.1182/blood-2015-11-679985

IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models

Helena Ågerstam, Nils Hansen, Sofia von Palffy, Carl Sandén, Kristian Reckzeh, Christine Karlsson, Henrik Lilljebjörn, Niklas Landberg, Maria Askmyr, Carl Högberg, Marianne Rissler, Kimmo Porkka, Hans Wadenvik, Satu Mustjoki, Johan Richter, Marcus Järås, Thoas Fioretos

Abstract

Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD341CD382) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NFkB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.

Original language	English
Journal	Blood
Volume	128
Issue number	23
Pages (from-to)	2683-2693
Number of pages	11
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2015-11-679985
Publication status	Published - 8 Dec 2016
Externally published	Yes

Keywords

Animals
Antibodies, Neoplasm/pharmacology
Female
Humans
Interleukin-1/metabolism
Interleukin-1 Receptor Accessory Protein/antagonists & inhibitors
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
Male
Mice
Mice, Knockout
Neoplasm Proteins/antagonists & inhibitors
Neoplastic Stem Cells/metabolism
Xenograft Model Antitumor Assays

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Ågerstam, H., Hansen, N., von Palffy, S., Sandén, C., Reckzeh, K., Karlsson, C., Lilljebjörn, H., Landberg, N., Askmyr, M., Högberg, C., Rissler, M., Porkka, K., Wadenvik, H., Mustjoki, S., Richter, J., Järås, M., & Fioretos, T. (2016). IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models. Blood, 128(23), 2683-2693. https://doi.org/10.1182/blood-2015-11-679985

Ågerstam, H, Hansen, N, von Palffy, S, Sandén, C, Reckzeh, K, Karlsson, C, Lilljebjörn, H, Landberg, N, Askmyr, M, Högberg, C, Rissler, M, Porkka, K, Wadenvik, H, Mustjoki, S, Richter, J, Järås, M & Fioretos, T 2016, 'IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models', Blood, vol. 128, no. 23, pp. 2683-2693. https://doi.org/10.1182/blood-2015-11-679985

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title = "IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models",

abstract = "Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD341CD382) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NFkB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.",

keywords = "Animals, Antibodies, Neoplasm/pharmacology, Female, Humans, Interleukin-1/metabolism, Interleukin-1 Receptor Accessory Protein/antagonists & inhibitors, Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy, Male, Mice, Mice, Knockout, Neoplasm Proteins/antagonists & inhibitors, Neoplastic Stem Cells/metabolism, Xenograft Model Antitumor Assays",

author = "Helena {\AA}gerstam and Nils Hansen and {von Palffy}, Sofia and Carl Sand{\'e}n and Kristian Reckzeh and Christine Karlsson and Henrik Lilljebj{\"o}rn and Niklas Landberg and Maria Askmyr and Carl H{\"o}gberg and Marianne Rissler and Kimmo Porkka and Hans Wadenvik and Satu Mustjoki and Johan Richter and Marcus J{\"a}r{\aa}s and Thoas Fioretos",

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doi = "10.1182/blood-2015-11-679985",

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T1 - IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models

AU - Ågerstam, Helena

AU - Hansen, Nils

AU - von Palffy, Sofia

AU - Sandén, Carl

AU - Reckzeh, Kristian

AU - Karlsson, Christine

AU - Lilljebjörn, Henrik

AU - Landberg, Niklas

AU - Askmyr, Maria

AU - Högberg, Carl

AU - Rissler, Marianne

AU - Porkka, Kimmo

AU - Wadenvik, Hans

AU - Mustjoki, Satu

AU - Richter, Johan

AU - Järås, Marcus

AU - Fioretos, Thoas

PY - 2016/12/8

Y1 - 2016/12/8

N2 - Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD341CD382) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NFkB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.

AB - Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD341CD382) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NFkB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.

KW - Animals

KW - Antibodies, Neoplasm/pharmacology

KW - Female

KW - Humans

KW - Interleukin-1/metabolism

KW - Interleukin-1 Receptor Accessory Protein/antagonists & inhibitors

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Neoplasm Proteins/antagonists & inhibitors

KW - Neoplastic Stem Cells/metabolism

KW - Xenograft Model Antitumor Assays

U2 - 10.1182/blood-2015-11-679985

DO - 10.1182/blood-2015-11-679985

M3 - Journal article

C2 - 27621309

SN - 0006-4971

VL - 128

SP - 2683

EP - 2693

JO - Blood

JF - Blood

IS - 23

ER -

IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models

Abstract

Keywords

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